3 TC Tablet and Solution

3TC in combination with zidovudine is indicated in the treatment of:

• HIV infected adults with progressive immunodeficiency (CD4 count < 500 cells/mm3) who have no prior antiretroviral therapy.
• HIV infected adults with progressive immunodeficiency who have been previously treated with zidovudine.

3TC is indicated as part of antiretroviral combination therapy for the treatment of HIV infected children.

3TC can be taken with food or without food. To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing. Alternatively, the tablets may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately. The professional information for zidovudine must be consulted for information on its dosage and administration.

Adults, adolescents and children weighing at least 25 kg:

• Oral solution: The recommended dose of lamivudine is 300 mg (30 ml) daily. This may be administered as 300 mg (30 ml) once daily or 150 mg (15 ml) twice daily.
• Tablets: The recommended dose of lamivudine is 300 mg daily. This may be administered as either 300 mg (two 150 mg tablets), once daily or 150 mg (one 150 mg tablet) twice daily.

Children:

Children < 3 months of age: The limited data available are insufficient to propose specific dosage recommendations (see section 5.2 Pharmacokinetic properties).

Oral Solution: For Children aged u2265 3 months and weighing less than 25 kg:

The recommended dose is 4 mg/kg twice daily or 8 mg/kg once daily up to a maximum of 300 mg daily. See section 4.4 Warnings and special precautions.

Tablets:

• Children weighing between 14 kg to < 20 kg: The recommended total daily dose of lamivudine is 150 mg. This may be administered as either one-half of a scored tablet twice daily or one whole tablet once daily.
• Children weighing u2265 20 kg to < 25 kg: The recommended total daily dose of lamivudine is 225 mg. This may be administered as either one-half of a scored tablet in the morning and one whole tablet in the evening, or one and a half scored tablets once daily.
• Children weighing at least 25 kg: The adult dosage of 150 mg twice daily or 300 mg once daily should be taken.

Renal Impairment: Lamivudine concentrations are increased in patients with moderate to severe renal impairment due to decreased clearance. The doses should therefore be reduced for patients with a creatinine clearance of less than 50 ml/min as shown in the table below. The same percentage reduction in dose applies for paediatric patients with renal impairment. When doses below 150 mg are needed the use of the oral solution is recommended.

Adults, adolescents and children weighing at least 25 kg:

Children u2265 3 months and weighing less than 25 kg:

Hepatic Impairment: No dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

The use of 3TC is contraindicated in patients with a known hypersensitivity to lamivudine or to any ingredients of 3TC.

3TC should not be used as monotherapy. Lactic acidosis/hyperlactataemia: Use of 3TC can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/u2113) and the serum bicarbonate and respond as follows:

• Lactate 2-5 mmol/u2113 with minimum symptoms: switch to agents that are less likely to cause lactic acidosis.
• Lactate 5-10 mmol/u2113 with symptoms and/or with reduced standard bicarbonate: Stop NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes, (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism).
• Lactate > 10 mmol/u2113: STOP all therapy (80 % mortality).

The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering 3TC to patients with known risk factors for liver disease. Treatment with 3TC should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or post-natally to nucleoside analogues. Apart from lactic acidosis/hyperlactataemia (see above) other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether these neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant sign and symptoms.

Fat redistribution: Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, elevated serum lipid and glucose levels have been observed either separately or together in some patients receiving combination antiretroviral therapy (see section 4.8 Undesirable effects). In addition, the lipodystrophy syndrome has a multi-factorial aetiology; with for example HIV disease status, older age and duration of antiretroviral treatment all playing important, possibly synergistic roles. The long-term consequences of these events are currently unknown. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Renal impairment: In patients with moderate to severe renal impairment, the terminal half-life of 3TC is increased due to decreased clearance. The dose of 3TC should therefore be adjusted (see section 4.2 Posology and method of administration).

Liver disease: Use of 3TC can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of 3TC has not been established in patients with significant underlying liver disorders/diseases. In case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant professional information for these medicines. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are tuberculosis, cytomegalovirus retinitis, cryptococcal meningitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Auto-immune disorders (such as Gravesu2019 disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be with atypical presentation.

Pancreatitis: Pancreatitis has been observed in patients receiving 3TC. However, it is unclear whether this was due to the medicine treatment or to underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of 3TC until diagnosis of pancreatitis is excluded.

Opportunistic infections: Patients receiving 3TC or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by physicians experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

The risk of HIV-transmission to others: Patients should be advised that antiretroviral therapy, including 3TC, has not been shown to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Patients with HIV and hepatitis B or C co-infection: Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant professional information for these medicines. Patients co-infected with HIV and HBV who discontinue 3TC should be closely monitored with both clinical and laboratory follow-up after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Discontinuation of 3TC therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.

Special patient population: Children: Children who at anytime received lamivudine oral solution concomitantly with other antiretroviral oral solutions in clinical trials experienced lower rates of virological suppression, had lower plasma lamivudine exposure and developed viral resistance more frequently than children receiving tablets (see section 5.2 Pharmacokinetic properties). 3TC ORAL SOLUTION given concomitantly with other antiretroviral oral solutions should be used for the treatment of HIV infection only when the benefits of treatment outweigh possible risks including lower virological suppression.

Oral Solution: Contains sucrose which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with the rare hereditary conditions such as fructose intolerance, glucose-galactose mal-absorption or sucrase-isomaltase insufficiency should not take 3TC ORAL SOLUTION.

The likelihood of interactions is low due to the limited metabolism and plasma protein binding and almost complete renal clearance. 3TC is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicines administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic transport system e.g. trimethoprim. Other active substances (e.g. ranitidine, cimetidine) are eliminated only in part by the mechanism and were shown not to interact with lamivudine.

Zidovudine: A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered when co-administered with 3TC. Zidovudine has no effect on the pharmacokinetics of lamivudine.

Zalcitabine: 3TC may inhibit the intracellular phosphorylation of zalcitabine when the two medicines are used concurrently. 3TC is therefore not recommended to be used in combination with zalcitabine.

Trimethoprim/sulphamethoxazole: Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40 % increase in 3TC exposure because of the trimethoprim component. However, unless the patient has renal impairment, no dosage adjustment of 3TC is necessary (see section 4.2 Posology and method of administration). 3TC has no effect on the pharmacokinetics of co-trimoxazole. The effect of co-administration of 3TC with higher doses of co-trimoxazole for the treatment of Pneumocystis carinii pneumonia and toxoplasmosis has not been studied.

Emtricitabine: Lamivudine may inhibit the intracellular phosphorylation of emtricitabine when the two medicines are used concurrently. Additionally, the mechanism of viral resistance for both lamivudine and emtricitabine is mediated via mutation of the same viral reverse transcriptase gene (M184V) and therefore the therapeutic efficacy of these medicines in combination therapy may be limited. 3TC is not recommended for use in combination with emtricitabine.

Pregnancy: There are no adequate and well-controlled trials in pregnant women and the safe use of lamivudine in human pregnancy has not been established. Consistent with passive transmission of the medicine across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery. Reproductive studies in animals have not shown evidence of teratogenicity and showed no effect on male or female fertility. There was some evidence of early embryolethality when administered to pregnant rabbits at exposure levels comparable to those achieved in information on placental transfer in humans. There have been reports of mild and transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of elevations in serum lactate is unknown. There have also been reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and 3TC exposure in utero or peri-partum has not been established.

Lactation: A study in lactating rats showed that, following oral administration, lamivudine was excreted in breast milk. Lamivudine is excreted in human breast milk at similar concentrations to those found in serum. Since the medicine may pass into breast milk, mothers taking 3TC should not breastfeed their infants.

No adverse effects regarding the patientu2019s ability to drive or operate machinery have been observed.

The following events have been reported during therapy for HIV disease with 3TC alone and in combination with zidovudine. The following convention has been utilised for the classification of undesirable effects: Very common ( u2265 1/10), common ( u2265 1/100, < 1/10), uncommon ( u2265 1/1 000, < 1/100), rare ( u2265 1/10 000, < 1/1 000), very rare (< 1/10 000).

Blood and lymphatic system disorders:

• Uncommon: neutropenia, anaemia, thrombocytopenia
• Very rare: pure red cell aplasia

Metabolism and nutrition disorders:

• Common: hyperlactataemia
• Rare: lactic acidosis (see section 4.4 Warnings and special precautions).
• Lipodystrophy (redistribution/accumulation of body fat (see section 4.4 Warnings and special precautions)).

Nervous system disorders:

• Common: headache
• Very rare: paraesthesia, peripheral neuropathy

Gastrointestinal disorders:

• Common: nausea, vomiting, upper abdominal pain, diarrhoea
• Rare: pancreatitis, rises in serum amylase

Hepatobiliary disorders:

• Uncommon: transient rises in liver enzymes (AST, ALT)

Skin and subcutaneous tissue disorders:

• Common: rash, alopecia

Musculoskeletal and connective tissue disorders:

• Common: arthralgia, muscle disorders
• Rare: rhabdomyolysis

General disorders and administration site conditions:

• Common: fatigue, malaise, fever.

Reporting of suspected adverse events: Reporting suspected adverse events after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u20186.04 Adverse Drug Reaction Reporting formu2019, found on line under SAHPRA publications, https://www.sahpra.org.za/Publications/index/8.

No specific signs or symptoms have been identified. In overdose, side effects can be precipitate and/or be of increased severity (see section 4.8 Undesirable effects). If overdosage occurs, the patient should be monitored, and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been studied.